Crosslinked hemoglobin product comprising tetrameric and oligomeric hemoglobin units

- Hemosol Inc.

A chemically modified, crosslinked hemoglobin product suitable for use as a hemoglobin based oxygen carrier comprises a mixture of hemoglobin species and consists essentially of about 40% tetrameric hemoglobin units of molecular weight about 64,000 daltons, up to 5% dimeric hemoglobin units of molecular weight about 32,000 daltons, and the balance oligomeric hemoglobin units of molecular weight up to about 60,000 daltons, the mixed product containing no polymeric hemoglobin species of molecular weight greater than 600,000 daltons. The product can be made directly by a crosslinking reaction under controlled conditions, without the need for separating therefrom high molecular weight species.

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Claims

1. A chemically modified, crosslinked hemoglobin product comprising a mixture of hemoglobin species and consisting essentially of about 40% tetrameric hemoglobin units of molecular weight about 64,000 daltons, up to 5% dimeric hemoglobin units of molecular weight about 32,000 daltons, and the balance being oligomeric hemoglobin units of molecular weight up to about 600,000 daltons, the mixture containing no polymeric hemoglobin species of molecular weight greater than 600,000 daltons.

2. The hemoglobin product of claim 1 wherein the tetrameric and oligo i neric hemoglobin units have chemical crosslinks between respective beta globin chains at position lysine-82 in the diphosphorlverate site.

3. The hemoglobin product of claim 2, produced by crosslinking hemoglobin by reaction with 0-raffinose, followed by chemical reduction to secondary amine groups of the crosslinks so formed.

Referenced Cited
U.S. Patent Documents
4529719 July 16, 1985 Tye
4822877 April 18, 1989 Inada et al.
4857636 August 15, 1989 Hsia
Other references
  • J. Courtois et al. A. Wickstrom. Action de l'acide periodique sur les tri et tetraholosides non reducteurs. I. Etude de raffinose. Bull. Soc. Chim. Biol. 32, 759 (1950). A.K. Mitra & A.S. Perlin. The Configuration of Glycoside Linkages in Oliogosaccharides. V. The Sucrose Linkage in Raffinose and Stachyose, Can. J. Chem. 35, 1079 (1957). Perlin. Glycol-cleavage Oxidation. In "The Carbohydrate-Chemistry and Biochemistry" 2nd Edition, Ed. W. Pigman and D. Horton. vol. 1B. Academic Press, 1980, p. 1167. G.L. Moore et al. Molecular Weight Determinations of O-Raffinose-Polymerized Human Hemoglobin Biomat. Art Cells & Immob. Biotech. 20, 293 (1992). J.C. Hsia et al. Pharmacokinetics Studies in the Rat on O-Raffinose Polymerized Human Hemoglobin Biomat., Art Cells & Immob. Biotech. 20 587 (1997). Chang & Varman, Effects of a Single Replacement of One of Ringer Lactate Hypertonic Saline/Dextran, 7g% Albumin . . . Biomat., Art. Cells & Immob. Biotech 20, 503 (1992). Vogel et al. Effects of O-Raffinose-Polymerized Human Hemoglobin on Coronary tone and Cardiac Function in Isolated Hearts. Biomat. Art. Cell 1& Immob. Biotech 20, 673 (1992). Keipert et al. The Role of the Kidneys in the Excretion of Chemically Modified Hemoglobins., Biomat., Art. Cells & Immob. Biotech. 20, 737 (1992). Kluger et al. Biochemistry., 1992, 31, 7551-9.
Patent History
Patent number: 5770727
Type: Grant
Filed: Jun 28, 1996
Date of Patent: Jun 23, 1998
Assignee: Hemosol Inc. (Etobicoke)
Inventors: Diana Pliura (Mississauga), Lawrence T. Wong (North York), Song Swee Er (Scarborough)
Primary Examiner: Mukund J. Shah
Assistant Examiner: Pavanaram K. Sripada
Law Firm: Ridout & Maybee
Application Number: 8/672,868
Classifications
Current U.S. Class: Porphyrins (including Hydrogenated; E.g., Chlorophyll, Etc.) (540/145); Hemoglobins Or Globins (530/385); 514/6
International Classification: C07D48722; C07K 1522;